Role of the renin-angiotensin system in the development of severe COVID-19 in hypertensive patients

Abstract

A new form of severe acute respiratory syndrome (SARS) caused by SARS-coronavirus 2 (CoV-2), called COVID-19, has become a global threat in 2020. The mortality rate from COVID-19 is high in hypertensive patients, making this association especially dangerous. There appears to be a consensus, despite the lack of experimental data, that angiotensin II (ANG II) is linked to the pathogenesis of COVID-19. This process may occur due to acquired deficiency of angiotensin-converting enzyme 2 (ACE2), resulting in reduced degradation of ANG II. Furthermore, ANG II has a critical role in the genesis and worsening of hypertension. In this context, the idea that there is a surge in the level of ANG II with COVID-19 infection, causing multiple organ injuries in hypertensive patients becomes attractive. However, the role of other components of the renin angiotensin system (RAS) in this scenario requires elucidation. The identification of other RAS components in COVID-19 hypertension may provide both diagnostic and therapeutic benefits. Here, we summarize the pathophysiologic contributions of different components of RAS in hypertension and their possible correlation with poor outcome observed in hypertensive patients with COVID-19.

Keywords: COVID-19; SARS-CoV-2; angiotensin II; hypertension; renin-angiotensin system.

Fig. 1.

Proposed model to explain why hypertensive patients with coronavirus disease 2019 (COVID-19) progress to an undesirable outcome. In hypertensive patients with COVID-19, we propose that there is a further increase in the level of ANG II as well as higher responsivity of angiotensin II type 1 receptor (AT₁R) to ANG II. The increase in the level of ANG II could be due to 1) a decrease in ANG II degradation by angiotensin-converting enzyme 2 (ACE2), prolylcarboxypeptidase (PRCP), and prolyl oligopeptidase (POP). ANG II could also decrease tissue ACE2 expression by increasing TNF-α converting enzyme (TACE)/ADAM17-mediated shedding, creating a positive feedback; 2) an increase in ANG II synthesis caused by an increase in renin and ACE activities. In addition to the increase in the level of ANG II, we also propose that the increase in expression and/or hyperresponsiveness of AT₁R in hypertensive patients could potentiate the effect of ANG II on different tissues affected by COVID-19. In this context, the inhibition of AT₁R could be a primary or coadjutant therapy for the treatment of patients with COVID-19. In agreement, a clinical trial of treatment with losartan is under way (NCT04328012). Red outline denotes reduced hypertension; blue outline denotes increased hypertension; dashed red outline denotes possible reduction in hypertension; dashed blue square denotes possibly increase in hypertension. *Possible therapeutic target; #possible biomarker.